Mexiletine. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in the treatment of arrhythmias

As a member of the class Ib antiarrhythmic drugs mexiletine's primary mechanism of action is blocking fast sodium channels, reducing the phase 0 maximal upstroke velocity of the action potential. It increases the ratio of effective refractory period to action potential duration, but has little effect on conductivity. Unlike quinidine it does not prolong QRS and QT (QTc) intervals. In the dosage range 600 to 900 mg daily mexiletine effectively suppresses premature ventricular contractions (PVCs) in 25% to 79% of patients, with or without underlying cardiac disease. In comparative studies the response rate was comparable to that with quinidine or disopyramide. However, the use of antiarrhythmic therapy in patients with asymptomatic arrhythmias is controversial. More importantly, mexiletine abolishes spontaneous or inducible ventricular tachycardia or fibrillation in the short term in 20% to 50% of patients with refractory arrhythmias. Arrhythmia suppression is maintained in 57% to over 80% of these early therapeutic successes in the long term, with mexiletine alone or in combination with another antiarrhythmic drug. As with other antiarrhythmic drugs, there is no substantial evidence that administration of mexiletine after acute myocardial infarction improves long term prognosis. Although the incidence of adverse effects associated with mexiletine is high, the majority are minor gastrointestinal or neurological effects which can be adequately controlled through dosage adjustment. Furthermore, mexiletine has minimal effects on haemodynamic variables, or on cardiac function in patients with or without pre-existing deterioration of left ventricular function, and it appears to have a low proarrhythmic potential. Thus, while the therapeutic efficacy of mexiletine for the prevention or suppression of symptomatic ventricular arrhythmias may be no greater than that of other antiarrhythmic drugs, and less than that of some (e.g. amiodarone), it is effective in a significant proportion of patients refractory to other treatments and can be administered without causing adverse haemodynamic effects to patients with complicating factors such as acute myocardial infarction or congestive heart failure.     

Sotalol. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use

Sotalol is a beta-adrenoceptor blocking agent devoid of intrinsic sympathomimetic activity, membrane stabilising actions and cardioselectivity. It lengthens repolarisation and the effective refractory period in all cardiac tissues independently of its antiadrenergic properties. Combining Class II and Class III antiarrhythmic properties, sotalol can be given either intravenously or orally and its pharmacokinetic properties permit long dosing (once or twice daily) intervals. Controlled and uncontrolled studies have established the efficacy of sotalol in mild-to-moderate essential hypertension and in angina of effort. Sotalol reduces anginal frequency and glyceryl trinitrate (nitroglycerin) consumption and increases exercise capacity during treadmill stress tests. In addition, although there is evidence that the drug reduces reinfarction rate in survivors of acute infarction, the data for reduction in sudden death rates in these patients are not as compelling as for other beta-blockers. However, comparative and additional long term studies are required before an accurate assessment of the use of sotalol in these disorders can be made. When used in the treatment of mild-to-moderate hypertension sotalol is more effective than placebo and comparable to other beta-blockers in reducing elevated blood pressures. In addition, a synergistic antihypertensive response is achieved when sotalol is combined with hydrochlorothiazide. Still, additional well-controlled comparative studies are required before the value of sotalol relative to other drug treatment regimens in the management of hypertension can be made. In preliminary studies sotalol appeared effective in most forms of supraventricular tachyarrhythmias with its effects being similar to those of other beta-blockers. However, preliminary data indicate that sotalol is likely to be more effective than than conventional beta-blockers in converting atrial flutter and fibrillation to sinus rhythm and maintaining stability post-conversion. Sotalol also appears to be a promising agent in the control of ventricular arrhythmias. In suppressing premature ventricular contractions it is at least as effective as procainamide. In ventricular tachycardia and fibrillation, intravenous sotalol (1.5 mg/kg), prevents reinduction by programmed electrical stimulation in 40 to 50% of cases if double stimuli are used. Both prevention of reinducible arrhythmia and the suppression of spontaneous arrhythmias on Holter recordings are predictive of a long term favourable clinical outcome. In patients with reduced ejection fractions, sotalol depresses ventricular function less than conventional beta-blockers.(ABSTRACT TRUNCATED AT 400 WORDS)     

Disopyramide. A reappraisal of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in cardiac arrhythmias

Disopyramide is a widely used class IA antiarrhythmic drug with a pharmacological profile of action similar to that of quinidine and procainamide. Over the past 10 years disopyramide has demonstrated its efficacy in ventricular and atrial arrhythmias. In therapeutic trials, usually involving small numbers of patients, the efficacy of disopyramide was comparable with that of mexiletine, perhexiline, tocainide, propafenone or prajmalium. Recent comparisons with quinidine have confirmed the similar efficacy and better tolerability of disopyramide. The suggestion from initial studies that disopyramide may be less effective than amiodarone or flecainide requires further investigation. In addition, studies have failed to demonstrate that the early administration of disopyramide after acute myocardial infarction decreases important arrhythmias or early mortality. Thus, disopyramide is now well established as an effective antiarrhythmic drug in ventricular and supraventricular arrhythmias although its role in therapy relative to that of recently introduced antiarrhythmic agents is not clear.     

Flunarizine. A review of its pharmacodynamic and pharmacokinetic properties and therapeutic use

Flunarizine is a 'selective' calcium entry blocker with a similar chemical structure and pharmacological profile to the related compound, cinnarizine. However, in contrast to cinnarizine it has a long plasma half-life and need only be given once a day. The majority of therapeutic trials in the prophylaxis of migraine, occlusive peripheral vascular disease and vertigo of central or peripheral origin have been placebo-controlled, and have shown that the drug produces significantly greater beneficial effects than placebo as evaluated by subjective and objective criteria. A small number of comparative studies have shown flunarizine to be at least as effective as pizotifen in migraine prophylaxis, and in a longer term study as effective as cinnarizine in vertigo of central origin. However, it has not been compared with other drugs which may be useful in these areas, such as methysergide in migraine prophylaxis, some antihistamines or phenothiazines in vertigo, or (understandably at this stage of its evolution) with surgical revascularisation in severe occlusive peripheral vascular disease. In preliminary placebo-controlled studies there was some evidence that flunarizine may improve impaired cognitive function in patients with cerebrovascular disorders, but such findings need further confirmation in additional carefully conducted studies. With a very long half-life, flunarizine may be given once daily; and drowsiness, the main side effect, can be minimised by taking the daily dose in the evening. Thus, it appears that flunarizine will offer a useful alternative in some therapeutic areas that can be difficult to manage with previously available therapy. However, a definitive statement on its relative place in therapy of such conditions must await a few well-controlled comparative studies.     

Bumetanide. A review of its pharmacodynamic and pharmacokinetic properties and therapeutic use

Bumetanide is a potent 'loop' diuretic for the treatment of oedema associated with congestive heart failure, hepatic and renal diseases, acute pulmonary congestion and premenstrual syndrome and in forced diuresis during and after surgery. Bumetanide may be given orally, intravenously or intramuscularly and produces a rapid and marked diuresis, and increased urinary excretion of sodium, chloride and other electrolytes (within 30 minutes) which persists for 3 to 6 hours. Its principal site of action is on the ascending limb of the loop of Henle, with a secondary action on the proximal tubule. Pharmacologically, bumetanide is about 40-fold more potent than frusemide (furosemide), with the exception of its effects on urinary potassium excretion where its potency is lower. Studies in patients with oedema due to congestive heart failure, pulmonary oedema or hepatic disease show that oral or intravenous bumetanide 0.5 to 2 mg/day produces results comparable to those with frusemide 20 to 80 mg/day. In acute pulmonary oedema, intravenous bumetanide produces a very rapid diuresis. Higher doses of bumetanide may be required (up to 15 mg/day) in patients with chronic renal failure or nephrotic syndrome. In these patients muscle cramps are not uncommon with bumetanide, but glomerular filtration rates are unaffected. In most studies, diuretic effects were accompanied by decreased bodyweight, abdominal girth and improvements in a variety of haemodynamic parameters. Comparison of bumetanide with frusemide at a dose ratio of 1 : 40 reveals no significant differences in clinical response with the exception of renal disease, where patients with oedema appear to respond better to bumetanide. Combination with thiazide diuretics enhances the clinical response to bumetanide. Potassium supplements and spironolactone may be beneficial additions to bumetanide where patients at risk of hypokalaemia can be identified. Clinically important side effects are infrequent, with audiological impairment occurring to a lesser extent than with frusemide. Bumetanide thus offers an important alternative to frusemide when a 'loop' diuretic is indicated.     

Xamoterol. A preliminary review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use

Xamoterol is a partial agonist at the beta 1-adrenoceptor. Haemodynamic studies indicate that xamoterol moderately increases myocardial contractility, improves diastolic relaxation and lowers left ventricular filling pressure at rest and during moderate exercise. At higher levels of sympathetic activity (e.g. strenuous exercise) it produces negative chronotropic responses whilst the reduced filling pressure is maintained. Studies in patients with mild to moderate chronic heart failure demonstrate an advantage for xamoterol 200mg twice daily over placebo and digoxin with respect to improvement in exercise capacity and symptoms. In limited trials to date the initial response seems to be maintained during periods of up to 12 months. Preliminary small studies suggest that xamoterol is useful in the treatment of some patients with angina pectoris, sinoatrial disease or postural hypotension, although further studies are needed to confirm its clinical role in such patients. Xamoterol appears to be generally well tolerated, but deleterious effects in a small number of patients with asthma, or severe heart failure due to dilated cardiomyopathy indicate the need for cautious use of xamoterol in patients with these diseases. Thus, xamoterol is a promising addition to the drugs available to the physician for treating patients with mild to moderate heart failure although further controlled studies are required to clearly establish its precise role.     

Gemfibrozil. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in dyslipidaemia

Gemfibrozil is a lipid-regulating agent which is generically classified as a fibric acid derivative, but which exhibits different pharmacological effects from other such drugs. Published data indicate that in patients with all types of dyslipidaemia (except type I) gemfibrozil 800 to 1200 mg/day is particularly effective in reducing total plasma triglyceride concentrations. The reduction in total plasma cholesterol is statistically significant with the most pronounced response occurring in patients with severe hypercholesterolaemia. Gemfibrozil also effectively increases high density lipoprotein cholesterol. In a 5-year double-blind prospective placebo-controlled study in over 4000 male patients with types IIa, IIb and IV primary dyslipidaemia (but without coronary symptoms), gemfibrozil 600mg twice daily significantly reduced the incidence of cardiac events (by 34%) compared with placebo, although overall mortality was not affected. In comparative studies with clofibrate similar reductions in plasma lipid levels have been observed, although these changes tend to be more favorable overall with gemfibrozil. Gastrointestinal symptoms and rash are the only side effects produced more frequently with gemfibrozil than with placebo. Although gemfibrozil is hepatotoxic in male rats, drug-induced pathological liver changes have not been reported in humans. Thus, gemfibrozil is an effective drug indicated for the treatment of severe hypertriglyceridaemia, and in certain patients with severe hypercholesterolaemia who are unresponsive to other standard therapies. In addition, it would appear to reduce the risk of cardiac events in patients with dyslipidaemia, although its effects on overall mortality remain speculative.     

Felodipine. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in hypertension

Felodipine is a dihydropyridine calcium antagonist which selectively relaxes vascular smooth muscle. By acting at peripheral arterioles, it lowers systemic vascular resistance and thereby produces substantial decreases in blood pressure and increases in cardiac output. Felodipine is indicated for the management of hypertension, and in patients with mild to moderate disease felodipine monotherapy markedly lowers blood pressure. It proved as effective as atenolol, and equivalent to hydrochlorothiazide, either with or without amiloride, in terms of antihypertensive activity. Comparative studies also demonstrated that once daily administration with an extended-release formulation provides equivalent antihypertensive efficacy to the same amount of drug administered twice daily as the standard tablets. As a second- or third-line treatment for patients with moderate to severe hypertension refractory to standard drug combinations, felodipine produced considerable reductions in blood pressure when added to beta-blockers and diuretics, either alone or in combination, in studies lasting up to 48 weeks. In comparative studies of multiple-drug treatments felodipine was found to have superior efficacy to hydralazine and prazosin, and was at least as effective as nifedipine, minoxidil and propranolol, when used with diuretics and/or beta-blockers. As an alternative to hydrochlorothiazide, in combination with beta-blockers, felodipine consistently controlled blood pressure in a greater percentage of patients and usually provided greater decreases in blood pressure. The main side effects with felodipine are ankle oedema, headache and flushing. Although the overall incidence of effects is quite high, they are usually mild in nature. Nevertheless, withdrawal due to side effects has been necessary in about 7% of patients overall. Thus, the efficacy of felodipine has been demonstrated in mild, moderate and severe hypertension. At the present time it seems particularly suitable as a second- or third-line treatment in refractory hypertension, but it also can be used as monotherapy for mild to moderate disease.     

Bezafibrate. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in hyperlipidaemia

Bezafibrate is a lipid-lowering drug, chemically related to clofibrate. At its recommended dosage of 200 mg 3 times daily, or alternatively 400 mg once daily as a sustained-release preparation, it produces substantial reductions in plasma triglyceride and cholesterol concentrations in patients with hypertriglyceridaemia and hypercholesterolaemia, respectively. Preliminary investigations indicate that a single daily dose of 400 mg in a sustained-release preparation is as effective as 200 mg 3 times daily. In patients with any type of hyperlipoproteinaemia bezafibrate also increases the plasma HDL-cholesterol concentration. These effects are equivalent in patients with primary hyperlipoproteinaemia or hyperlipoproteinaemia secondary to diabetes or renal disease, although dosage adjustment is important in the latter group. During long term therapy (2 to 4 years) the influence of bezafibrate on the lipid profile is sustained. The lipid-lowering effects of bezafibrate are at least equivalent to those of clofibrate, fenofibrate, colestipol, probucol or sustained release etofibrate. In addition, the increase in HDL-cholesterol tends to be at least as great as with all alternative treatments studied. Bezafibrate is rapidly eliminated, and thus does not accumulate during prolonged administration in patients with normal renal function. Experimental studies have shown bezafibrate to have a complex range of effects on lipoproteins and on the enzymes and receptors involved in lipid metabolism. However, its exact mechanism of lipid-lowering action is unclear. Bezafibrate enhances anticoagulation in hyperlipoproteinaemic patients requiring anticoagulant therapy, and preliminary investigations indicate that it reduces the plasma fibrinogen concentration, especially in patients with hyperfibrinogenaemia. These properties of bezafibrate could contribute to an antiatherogenic effect of the drug, but further investigation is required to establish the drug's potential as chronic therapy in patients with hyperfibrinogenaemic atherosclerosis. Adverse reactions to bezafibrate have largely been restricted to gastrointestinal disturbances, with some cutaneous reactions and central nervous system effects. The incidence of side effects has been no greater than with comparative lipid-lowering drugs. In patients with renal disease, a few cases of marked elevation of serum creatine phosphokinase and myoglobin, and associated muscle cramps, have been reported (diagnosed as rhabdomyolysis). Hepatic enzyme induction by bezafibrate in rats results in hepatomegaly, but there has been no case of significant hepatotoxicity in man.(ABSTRACT TRUNCATED AT 400 WORDS)     

Guanadrel. A review of its pharmacodynamic and pharmacokinetic properties and therapeutic use in hypertension

Guanadrel sulphate is an orally active peripheral sympathetic inhibitor (adrenergic neuron-blocking drug). In comparative studies, guanadrel was comparable in efficacy with guanethidine or methyldopa in mild to moderately severe hypertension, although generally it caused fewer central nervous system side effects than methyldopa and less orthostatic dizziness and diarrhoea than guanethidine. However, its efficacy in patients whose blood pressure remains inadequately controlled by other drugs (except diuretics alone) has yet to be adequately demonstrated. Guanadrel has a rapid onset of action and a half-life of about 10 hours, thus dose titration can be achieved more rapidly than with guanethidine, and twice daily administration is appropriate. Generally, guanadrel has been well tolerated, withdrawal of treatment due to adverse effects seldom being necessary. Thus, guanadrel appears to be a suitable alternative to methyldopa for the treatment of mild to moderately severe hypertension not controlled adequately by diuretics alone.     

Fenofibrate. A review of its pharmacodynamic and pharmacokinetic properties and therapeutic use in dyslipidaemia

Fenofibrate is a lipid-regulating drug which is structurally related to other fibric acid derivatives, such as clofibrate. At the recommended dosage of 200 to 400 mg daily, it produces substantial reductions in plasma triglyceride levels in hypertriglyceridaemic patients and in plasma total cholesterol levels in hypercholesterolaemic patients. High density lipoprotein (HDL)-cholesterol levels are generally increased in patients with low pretreatment values. Fenofibrate appears to be equally effective in diabetic patients with hyperlipoproteinaemia without adversely affecting glycaemic control. The influence of fenofibrate on the plasma lipid profile is sustained during long term (2 to 7 years) treatment. Comparative studies conducted to date have involved only small groups of patients--in overall terms fenofibrate was at least as effective as other fibrates, but larger comparative studies are needed before valid conclusions on its relative efficacy compared with nonfibrate lipid-lowering drugs can be drawn. The influence of fenofibrate on morbidity and mortality from cardiovascular disease has not been studied. Clinical adverse reactions to fenofibrate have mainly consisted of gastrointestinal disturbances, headache and muscle cramps. Transient elevations in transaminase and creatine phosphokinase levels commonly occur. Isolated cases of hepatitis with substantially elevated transaminase levels have been reported. Fenofibrate induces hepatomegaly, peroxisome proliferation and hepatic carcinomas in rodents, but this type of hepatotoxicity has not been observed in humans. The biliary lithogenic index is increased by fenofibrate, but this has not been shown to have increased the incidence of gallstones in treated patients. Thus, fenofibrate offers an effective and well tolerated alternative to clofibrate or other fibric acid derivatives, but its relative efficacy and tolerability compared with other types of lipid-lowering drugs, and its effect on cardiovascular morbidity and mortality, remain to be clarified.     

Isradipine. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in cardiovascular disease

Isradipine, a dihydropyridine derivative, inhibits the inward calcium flux through 'slow' channels of cardiac and vascular tissue, thereby eliciting potent coronary, cerebral and peripheral vasodilatation. In comparison with other calcium channel blockers the drug offers the advantages of minimal cardiodepressant activity, a selective action on the coronary and skeletal muscle vasculature, and a prolonged vasodilatory action. Clinical trials indicate that isradipine is an effective antihypertensive agent, suitable as monotherapy or in combination with beta-blockers, diuretics or ACE inhibitors, for long term treatment of mild to moderate hypertension. Preliminary findings suggest that the drug has a potential role in the treatment of chronic stable angina and, possibly, congestive heart failure. Adverse effects associated with the vasodilatory action of isradipine are generally mild, transient and well-tolerated, and are similar to those encountered with other calcium channel blockers. Thus, isradipine appears to offer a useful alternative to other dihydropyridine derivatives currently employed for the treatment of mild to moderate hypertension and, to a lesser extent, chronic stable angina. While its relative freedom from serious adverse effects may prove of value, its place in therapy vis-à-vis the established calcium channel blockers requires further clarification.     

Amlodipine. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in cardiovascular disease.

Amlodipine, a basic dihydropyridine derivative, inhibits the calcium influx through 'slow' channels in peripheral vascular and coronary smooth muscle cells, thus producing marked vasodilation in peripheral and coronary vascular beds. Short to medium term clinical trials indicate that amlodipine is effective as both an antianginal agent in patients with stable angina pectoris and an antihypertensive agent in patients with mild to moderate hypertension. In small comparative studies amlodipine was at least as effective as 'standard' agents, including atenolol, verapamil, hydrochlorothiazide or captopril in hypertension, and diltiazem or nadolol in angina pectoris. Amlodipine is well tolerated, and does not appear to cause some of the undesirable effects often associated with other cardiovascular agents (e.g. adverse changes in serum lipid patterns, cardiac conduction disturbances, postural hypotension). The most common adverse effects associated with amlodipine therapy--oedema and flushing--are related to the vasodilatory action of the drug, and are generally mild to moderate in severity. Thus, amlodipine seems to provide a useful alternative to other agents currently available for the treatment of essential hypertension and chronic stable angina pectoris, with certain pharmacodynamic and tolerability properties that should be advantageous in many patients.     

Acecainide (N-acetylprocainamide). A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in cardiac arrhythmias.

Acecainide (N-acetylprocainamide), the N-acetylated metabolite of procainamide, is a Class III antiarrhythmic agent. It can be given either intravenously or orally, and is eliminated primarily by renal excretion. In a small number of noncomparative and placebo-controlled short term therapeutic trials acecainide markedly reduced premature ventricular beats and prevented induction of ventricular tachycardia in more than 70% of patients following intravenous administration and in about 50% after oral administration. Acecainide was effective in about one-quarter of patients refractory to other antiarrhythmic drugs. Interpretation of its effectiveness following long term oral therapy is complicated by the limited number of patients, and patients discontinuing due to adverse effects or lack of efficacy. However, about 40% of the small number treated for extended periods were controlled for periods of 6 months to 3 to 4 years. Comparative studies with other antiarrhythmic drugs have not been undertaken apart from a small study in atrial flutter where acecainide was better than quinidine plus digoxin. Thus, although further clinical experience is required before the relative place of acecainide in therapy can be determined, the drug nevertheless appears to offer advantages over procainamide, particularly with respect to the reduced formation of antinuclear antibodies.     

Tamoxifen. A reappraisal of its pharmacodynamic and pharmacokinetic properties, and therapeutic use

Tamoxifen, a non-steroidal antioestrogen, represents a significant advance in treatment of female breast cancer. In trials of tamoxifen as postsurgical adjuvant treatment of early breast cancer, disease-free survival is consistently prolonged, representing an enhanced quality of life in association with tamoxifen's favourable adverse effect profile. Moreover, overview analysis indicates a survival benefit of approximately 20% at 5 years for all women, most clearly evident in women over 50 years, while a survival benefit independent of menopausal, nodal or oestrogen receptor status has been demonstrated in some individual trials. Thus, for postmenopausal women, tamoxifen is clearly optimal adjuvant treatment, although the relative benefit of adjuvant chemotherapy in node-negative patients requires clarification. A survival benefit for women under 50 has not been clearly demonstrated in overview analysis, but is not precluded by these rather limited data, and adjuvant treatment of premenopausal women with tamoxifen may also warrant serious consideration. Response rates to tamoxifen in advanced breast cancer are around 30 to 35%, increasing with patient selection for oestrogen receptor positivity. Tamoxifen must be regarded as first-line endocrine treatment in postmenopausal women, and may represent an alternative to first-line ovarian ablation in premenopausal women. An emergent role in primary therapy of elderly and frail patients with operable disease is apparent. Tamoxifen is also of benefit following surgery in male breast cancer, and may have a role as first-line endocrine treatment. Tamoxifen also has a potential role in other hormone-sensitive malignancies such as pancreatic carcinoma, and in treatment of benign breast disease. Finally, tamoxifen has a place in treatment of male and female infertility. because of adverse effects is rarely necessary. The most frequent adverse effects are related to the drug's anti-oestrogenic activity, and include hot flushes, nausea and/or vomiting, vaginal bleeding or discharge, and menstrual disturbances in premenopausal patients. Thus, tamoxifen continues to play a major role in management of female breast cancer in both early and advanced stages of disease, with a place also in treatment of male breast cancer and of infertility.     

Zidovudine. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy

Zidovudine (azidothymidine) is a thymidine analogue antiretroviral drug active against human immunodeficiency virus (HIV). In acquired immunodeficiency syndrome (AIDS) and AIDS-related complex (ARC) patients, orally and intravenously administered zidovudine is effective in reducing the incidence of opportunistic infections and neoplasms, increasing helper T lymphocyte numbers, and improving survival rates and quality of life. Adverse effects include serious haematological abnormalities and severe headache, abdominal discomfort, nausea, myalgia and insomnia. In addition, neutropenia and other anaemias frequently limit zidovudine therapy and may result in a need for multiple blood transfusions, dose reductions or withdrawal of the drug. However, despite these problems and the lack of information about some aspects of zidovudine use, zidovudine provides a major hope for HIV-infected patients, and it has rapidly become the standard therapy for improving the quality and duration of the lives of AIDS and ARC patients.     

Azelastine. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential

Azelastine is an antiallergic agent which demonstrates histamine H1-receptor antagonist activity and also inhibits histamine release from mast cells following antigen and non-antigen stimuli. Azelastine antagonises histamine- and leukotriene-induced bronchospasm in animal studies and reduces airway responsiveness to inhaled antigen or distilled water, and exercise challenge. In comparative studies, orally administered azelastine in doses up to 4 mg/day consistently relieved symptoms in patients with seasonal or perennial rhinitis - comparable to inhaled sodium cromoglycate (cromolyn sodium) 80 mg/day, oral chlorpheniramine (chlorphenamine) and oral terfenadine 120 mg/day. In addition, azelastine administered as an intranasal spray was as effective as oral terfenadine 120 mg/day and intranasal budesonide 0.4 mg/day in alleviating symptoms of rhinitis. Azelastine is also a potent antiasthmatic agent which produces significant and long lasting bronchodilation in patients with bronchial asthma. The drug is superior to placebo and comparable to oral ketotifen 2 mg/day and sustained release theophylline 700 mg/day when administered as a twice daily oral 4 mg dose. Azelastine is generally well tolerated: the most common adverse effects are altered taste perception and drowsiness. Adverse effects are mild and transient and result in withdrawal of treatment in less than 2% of patients. In a comparative study oral azelastine 2 or 4 mg/day produced no more sedation than terfenadine 120 mg/day. Thus, barring unexpected findings with wider clinical use, azelastine offers an effective and well tolerated choice of treatment for patients with allergic rhinitis and/or bronchial asthma, which may be particularly beneficial in patients in whom inhaled drug treatment is contraindicated.     

Pirprofen. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy

Pirprofen is a non-steroidal anti-inflammatory drug, related structurally to drugs such as ibuprofen, ketoprofen and naproxen. Published clinical trials indicate that pirprofen 600 to 1200 mg/day as 2 or 3 divided doses is a suitable alternative to usual therapeutic dosages of aspirin, flurbiprofen, ibuprofen, indomethacin, ketoprofen, naproxen, piroxicam and sulindac in the treatment of rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, musculoskeletal disorders and non-articular rheumatism. More studies are required to evaluate its potential relative to other commonly used drugs in the treatment of gout, juvenile rheumatoid arthritis and dysmenorrhoea. In patients with acute postsurgical, trauma or cancer pain, single oral or intramuscular doses of pirprofen 200 to 400mg provide equivalent analgesic activity to usual therapeutic doses of aspirin, diflunisal, ketoprofen, noramidopyrine, paracetamol and pentazocine. As with other non-steroidal anti-inflammatory drugs, gastrointestinal complaints are the most frequently reported side effects. At equivalent analgesic or anti-inflammatory dosages, pirprofen probably causes fewer side effects than aspirin and appears to be as well tolerated as the other agents with which it has been compared. Long term tolerability, particularly compared with some of the newer, purportedly less gastrotoxic agents or formulations, needs to be investigated further. Pirprofen does not appear likely to offer any particular advantage with respect to efficacy and tolerability over other non-steroidal anti-inflammatory drugs, except aspirin. However, as no one agent is the most suitable drug for all patients requiring such therapy, pirprofen may be considered along with other drugs of this type in the therapy of arthritic conditions and acute pain states.     

Pentoxifylline. A review of its pharmacodynamic and pharmacokinetic properties, and its therapeutic efficacy

Pentoxifylline (oxpentifylline) is an orally active haemorheological agent for the treatment of peripheral vascular disease, cerebrovascular disease and a number of other conditions involving a defective regional microcirculation. Pentoxifylline acts primarily by increasing red blood cell deformability, by reducing blood viscosity and by decreasing the potential for platelet aggregation and thrombus formation. Extensive open and placebo-controlled studies have shown that pentoxifylline 600 to 1200 mg/day for at least 6 weeks is associated with subjective and objective improvements in 60 to 100% of patients with peripheral vascular disease. The most commonly assessed clinical parameter, walking distance, is usually improved by about 100%, although much greater improvements have also been documented. Other parameters which have been clearly improved include lower limb rest pain, paraesthesia, muscle blood flow, cramps and leg ulcers. Pentoxifylline has produced consistently better results than placebo, and in those studies using comparative drugs, better results than nylidrin, adenosine and naftidrofuryl. In patients with cerebrovascular disorders, open studies with pentoxifylline, usually at a dosage of 600 to 1200 mg/day (300 to 600 mg/day in Japan), have shown marked overall clinical improvements in about 85% of patients. Symptomatic improvements in rehabilitation psychometric tests, neuromotor and speech deficits and other subjective symptoms have accompanied increased cerebral blood flow, particularly to ischaemic areas. Pentoxifylline would appear to be useful in most types of cerebrovascular disease including transient ischaemic attacks, sequelae of cerebral thrombosis and haemorrhage, and chronic ischaemic disorders. In patients with chronic cerebrovascular disease pentoxifylline 600 to 1200 mg/day conferred significant clinical benefit compared with placebo and in isolated studies proved to be superior to drugs such as co-dergocrine mesylate, adenosine and pyrithioxine. Preliminary studies indicate that pentoxifylline may also prove useful in vaso-occlusive crises of sickle cell disease, some hearing disorders, disorders of eye circulation, high altitude sickness and asthenozoospermia. Pentoxifylline is usually well tolerated when administered as the conventional controlled release formulation, gastrointestinal symptoms (about 3%) being the most common complaint, although these and other adverse effects have not occurred to a significantly greater extent than with placebo. Thus, pentoxifylline offers a well-tolerated and effective alternative to the treatment options available for patients with peripheral vascular disease.(ABSTRACT TRUNCATED AT 400 WORDS)     

Flutamide. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic use in advanced prostatic cancer.

Flutamide, a nonsteroidal antiandrogenic drug devoid of hormonal agonist activity, is used in the treatment of advanced prostate cancer. In previously untreated patients, flutamide 750 mg daily given alone is of comparable efficacy to diethylstilbestrol (stilboestrol) 1 or 3 mg daily and estramustine 560 or 840 mg daily, but has the potential advantages of fewer cardiovascular effects and maintenance of some sexual potency. Its greatest therapeutic potential is as a component of combination androgen blockade, where administration with an agonist analogue of gonadotrophin-releasing hormone (GnRH) [luteinising hormone-releasing hormone (LH-RH)] in both initial uncontrolled and randomised studies increased survival time relative to GnRH agonist monotherapy or orchidectomy. Subsequent multicentre trials, however, have been unable to confirm an improvement in survival time. Thus, while there seems to be little doubt that flutamide prevents the initial disease flare caused by GnRH agonists, an improvement in remission rate and survival remains contentious. Flutamide is generally well tolerated and is suitable monotherapy in patients with previously untreated advanced prostatic cancer who wish to preserve sexual potency. However, full assessment of the role of combination androgen blockade awaits publication of the final results of ongoing multicentre trials.